CD44, a non-kinase transmembrane glycoprotein, is overexpressed in various cell types, including cancer stem cells, and exhibits alternative spliced variants that play significant roles in cancer development and progression. Hyaluronan, the primary ligand for CD44, binds to and activates CD44, leading to the activation of signaling pathways that promote cell proliferation, survival, cytoskeletal changes, and motility. CD44 has two main isoforms: standard (CD44s) and variant (CD44v) isoforms, which have distinct functional roles. CD44v isoforms contain additional peptide motifs that can interact with and sequester growth factors and cytokines, acting as coreceptors to facilitate cell signaling. CD44v isoforms are expressed in metastatic tumors and are associated with epithelial-to-mesenchymal transition (EMT) and adaptive plasticity of cancer cells. The clinicopathological implications of CD44 in promoting tumorigenesis suggest that it may be a molecular target for cancer therapy. Therapeutic strategies targeting CD44 or reducing its expression are under development, including neutralizing antibodies, shRNAs, ectodomain mimics, and aptamers. Understanding the structural and functional properties of CD44, its regulation, and the potential for targeting it for cancer therapy is crucial.CD44, a non-kinase transmembrane glycoprotein, is overexpressed in various cell types, including cancer stem cells, and exhibits alternative spliced variants that play significant roles in cancer development and progression. Hyaluronan, the primary ligand for CD44, binds to and activates CD44, leading to the activation of signaling pathways that promote cell proliferation, survival, cytoskeletal changes, and motility. CD44 has two main isoforms: standard (CD44s) and variant (CD44v) isoforms, which have distinct functional roles. CD44v isoforms contain additional peptide motifs that can interact with and sequester growth factors and cytokines, acting as coreceptors to facilitate cell signaling. CD44v isoforms are expressed in metastatic tumors and are associated with epithelial-to-mesenchymal transition (EMT) and adaptive plasticity of cancer cells. The clinicopathological implications of CD44 in promoting tumorigenesis suggest that it may be a molecular target for cancer therapy. Therapeutic strategies targeting CD44 or reducing its expression are under development, including neutralizing antibodies, shRNAs, ectodomain mimics, and aptamers. Understanding the structural and functional properties of CD44, its regulation, and the potential for targeting it for cancer therapy is crucial.